Ear Structure
The ear, which is the organ of hearing and balance, consists of the outer, middle, and inner ear. The outer, middle, and inner ear function together to convert sound waves into nerve impulses that travel to the brain, where they are perceived as sound. The inner ear also helps to maintain balance.
Outer Ear
The outer ear consists of the external part of the ear (pinna or auricle) and the ear canal (external auditory meatus). The pinna consists of cartilage covered by skin and is shaped to capture sound waves and funnel them through the ear canal to the eardrum (tympanic membrane), a thin membrane that separates the outer ear from the middle ear.
Middle Ear
The middle ear consists of the eardrum and a small air-filled chamber containing a chain of three tiny bones (ossicles) that connect the eardrum to the inner ear. The ossicles are named for their shapes. The hammer (malleus) is attached to the eardrum. The Eustachian tube, a small tube that connects the middle ear with the back of the nose, allows outside air to enter the middle ear. This tube, which opens when a person swallows, helps maintain equal air pressure on both sides of the eardrum and prevents fluid from accumulating in the middle ear. If air pressure is not equal, the eardrum may bulge or retract, which can be uncomfortable and distort hearing. The Eustachian tube's connection with the middle ear explains why upper respiratory infections (such as the common cold), which inflame and block the Eustachian tube, can lead to middle ear infections or changes in middle ear pressure, resulting in pain.
Inner Ear
The inner ear (labyrinth) is a complex structure consisting of two major parts: the cochlea, the organ of hearing; and the vestibular system, the organ of balance. The vestibular system consists of the saccule and the utricle, which determine position sense, and the semicircular canals, which help maintain balance.
The cochlea, a hollow tube coiled in the shape of a snail's shell, is filled with fluid. Within the cochlea is the organ of Corti, which consists, in part, of about 20,000 specialized cells, called hair cells. These cells have small hairlike projections (cilia) that extend into the fluid. Sound vibrations transmitted from the ossicles in the middle ear to the oval window in the inner ear cause the fluid and cilia to vibrate. Hair cells in different parts of the cochlea vibrate in response to different sound frequencies and convert the vibrations into nerve impulses. The nerve impulses are transmitted along fibers of the cochlear nerve to the brain. Despite the protective effect of the acoustic reflex, loud noise can damage and destroy hair cells. Once a hair cell is destroyed, it does not appear to regrow. Continued exposure to loud noise causes progressive damage, eventually resulting in hearing loss and sometimes noise or ringing in the ears (tinnitus). The semicircular canals are three fluid-filled tubes at right angles to one another. The canals contain hair cells that respond to the movement of the fluid. If the semicircular canals malfunction, as may occur in an upper respiratory infection and other conditions both temporary and permanent, a person's sense of balance may be lost or a whirling sensation (vertigo) may develop.
Use of Ear Drops for the Treatment of Ear Disorders
Currently, ear care products (otic, ototopical agents) are administered to the treated subject in the form of drops. Generally, ear drops are based on antibiotic agents, antibacterial agents, antifungal agents, antiviral agents, steroid derivatives, anti-inflammatory agents, analgesic compounds or a mixture thereof. For example, initial therapy for acute otitis externa (AOE) is typically a combination consisting of neomycin, polymyxin B and a steroid (commercially available as for example, Cortisporin™) (Lee L, Steinberg I, Gill M A. Management of Ear Infections. Cal Parma 2001; Spring; 56-64). Current medications also include quinolone derivatives i.e. Ciprofloxacin 1% or Oflaxacin 0.3%. Other compositions of ear drops are further described in U.S. Pat. Nos. 5,401,741; 5,679,665; 5,965,549; and 5,843,930 the entire disclosures of which are hereby incorporated by reference.
Another common use of ear drops is for ear pain treatment. Ear pain (otalgia) can range from mild discomfort or a feeling of fullness to severe intense pain, and can be very unpleasant and even unbearable, especially in children. Usually, ear pain results from pathological conditions of the external or middle ear. Such pathological conditions, discussed lengthily above, may be caused by infection, trauma, or blockage of the ear. Briefly, common trauma may result by use of a cotton swab to clean the ear or as a result of sudden changes in pressure such as changes in altitude when flying or diving. Blockage of the ear canal can be caused by excessive earwax (cerumen) or foreign objects such as beads, beans or bugs. Infections of the ears include otitis externa (swimmer's ear), otitis media, an infection of the inner ear, mastoiditis and other pathologies as mentioned above and fully described in the literature. Other disorders that may cause ear pain are allergic reactions, ruptured eardrum, acute sinusitis, chronic sinusitis, tooth abscess, sore throat with referred pain to the ears, Meniere's disease, tumors of the ear, which may be cancerous or benign and temporomandibular joint (jaw) syndrome.
Currently available analgesic ear drops used for the treatment of ear pain usually contain an analgesic compound such as: benzocaine, tetracaine, amethocaine antipyrine and/or phenazone.
Ear drops are usually administered to the treated ear by tilting the head of a treated subject to the side, instilling drops of the medicament into the ear and maintaining the adopted position for few minutes, in order to allow the medicine to reach the interior of the ear. A clean cotton-wool plug may be inserted into the opening of the ear to prevent the medication from leaking out. In addition, in order to prevent contamination of the ear drops, the bottle tip must not be in contact with any surface, including the hands and the ear itself.
A number of drawbacks are associated with ototopical administration in the form of drops. In principle, ear drops exert their effect by direct contact with the affected area. If administration is poor (e.g., the head of the treated subject is not tilted long enough) and the drops cannot reach the infected area, the active agent cannot be effective. Delivery can be impaired in a number of different ways, including failure of the drops to enter the ear canal, short contact period of the medicament with the ear canal since the drops are naturally washed out or because the head of the treated subject is not tilted long enough for the agent to reach its target. In addition, the form of the current medicaments as ear drops is difficult to apply, especially to small children and animals that tend not to cooperate mainly due to the difficulty in maintaining a sedentary position for a prolonged period (several minutes). Cotton wool that is usually added to the ear after administering the drops, might be pushed inside the ear canal and is difficult to remove. Also, the existing drugs often inadequately address a patient's needs for efficacy and aesthetics (e.g. running of drops on face and neck), and the failure to address those needs may decrease patient compliance and impair overall treatment.
Attempts have been made to provide alternate devices and methods for delivery of medication to the ear canal. U.S. Pat. No. 6,764,470 teaches an ear plug medication administration device that maintains the medication in the ear canal. The device comprises a resilient casing comprising a barrier defining an enclosed reservoir for a medication. The casing is configured to be compressed to fit within the ear, and configured to eject the medication upon being compressed. This device requires considerable handling and is awkward for use with infants and children.
U.S. Pat. No. 4,241,048 discloses anesthetic compositions comprising a therapeutically effective amount of powdered Benzocaine. In particular embodiments, the composition is in the form of a foamable liquid, aerosol product or a solid. In the disclosure, it is noted that the compositions “can also be applied to burns, sunburn, poison ivy, insect bite, otic (ear), teething (gums) preparations, etc.”
US patent application publication number 20020064541, and U.S. Pat. Nos. 5,744,166 6,238,650 are directed to compositions for topical application in the form of microcapsules or microspheres.
The above disclosures neither teach nor suggest a composition or use of a foam or mousse to treat ear disorders.
Foam Delivery of Therapeutic Agents
Various foams useful for the delivery of therapeutic agents to the skin and body cavities are taught in the art. U.S. Pat. No. 6,730,288 discloses aerosol foam, also referred to as “mousse”, for topical administration of insoluble pharmaceutically active ingredients. The composition comprises an occlusive agent in an amount sufficient to form an occlusive layer on the skin. Administration of mousse to the ear is neither taught nor suggested.
International patent application publication WO 2004/037225 teaches alcohol-free cosmetic or pharmaceutical foams suitable for delivery of both water soluble and oil-soluble pharmaceutical agents. That patent teaches foams useful for topical application of pharmaceutical agents to body cavities.
U.S. Pat. No. 4,915,934 teaches a quick-breaking foamable biocidal composition, comprising a quick breaking alcoholic foaming agent comprising: an aliphatic alcohol, a fatty alcohol, water and a surface-active agent.
U.S. Pat. No. 5,759,520 discloses a method for treating conditions of the gastro-intestinal tract, comprising administering from a pressurized container an aqueous foamable composition comprising a major amount by weight of water; a foaming agent consisting of a water-immiscible liquified gas; at least one emulsifying surfactant; Xanthan gum; and an effective amount of a pharmaceutically active substance; the composition having a delayed foaming action.
U.S. Pat. No. 6,126,920 teaches methods of treating various skin diseases, including scalp psoriasis, utilizing a foamable pharmaceutical composition comprising a corticosteroid active substance, a quick-break foaming agent, a propellant and a buffering agent. The present invention is preferably intended to increase the residence time of a pharmaceutical composition in the ear, and does not preferentially use quick breaking foams.
U.S. Pat. Nos. 5,393,528 and 5,529,782 teach a device comprising a dissolvable film made of polyvinyl alcohol, polyethylene oxide, hydroxypropylmethyl cellulose and mixtures thereof and a method for the delivery of medication. Nitrogen gas may be introduced while mixing to form frothy foam. Those patents do not disclose administration of foam into a bodily cavity.
UK Patent GB0933486 teaches liquid non-aqueous foamable aerosol compositions and provides a general disclosure of stable foams. That disclosure mentions in passing that “a quick breaking foam may be required for applying a uniform coating of a non-aqueous liquid to an irregular or inaccessible surface such as the middle ear” but neither teaches nor suggests compositions for the treatment of ear disorders or methods of administering a composition to the outer ear, which is the more appropriate method of application.
U.S. Pat. No. 6,521,213, teaches a method for preventing otitis externa by administering an aerosolized mixture of lipid crystals to the epithelial lining of the external auditory canal. The patent further teaches a method of treating otitis extema by administering a mixture of lipid crystals further comprising a therapeutic agent. The present invention does not use lipid crystals.
U.S. Pat. No. 4,305,936 relates to a composition comprising at least one corticosteroid, for topical or local application to the skin or body cavity. According to one embodiment of that patent, the preparation can produce a foam when packaged in the form of an aerosol or non-aerosol foam-forming closure system.
None of the above disclosures teach or suggest the delivery of medicaments specifically to the ear in the form of a foam or mousse.
Thus, there is a widely recognized need for, and it would be highly advantageous to have convenient and practical forms of medicaments to treat ear disorders, that ma overcome all drawbacks related to the use of such medicaments in the form of drops.